Stable pergolide mesylate and process for making same

ABSTRACT

A formulation and a method for manufacturing pergolide mesylate is disclosed whereby substantially stable pergolide mesylate can be manufactured without having to introduce stabilizing additives.

[0001] The instant application claims priority to the U.S. Provisional Application No. 60/223,774, filed Aug. 8, 2000 by the same inventors.

FIELD OF THE INVENTION

[0002] The present invention relates to the field of pharmaceuticals and, more particularly, to a formulation and a process of manufacturing stable pergolide mesylate.

BACKGROUND OF THE INVENTION

[0003] Pergolide Mesylate is an ergot derivative dopamine receptor agonist at both D₁ and D₂receptor sites. Pergolide mesylate is chemically designated as 8(beta)-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate, and has the following structural formula:

[0004] The formula weight of the base is 314.5; 1 mg of base corresponds to 3.18 μmol.

[0005] Pergolide Mesylate is sold under the trade name PERMAX® and is provided for oral administration in tablets containing 0.05 mg (0.159 μmol), 0.25 mg (0.795 μmol), or 1 mg (3.18 μmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05-mg tablet also contains methionine, and the 0.25-mg tablet also contains F D & C Blue No. 2.

[0006] Pharmaceutically, pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1,000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson's disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating post-synaptic dopamine receptors in the nigrostriatal system.

[0007] Information on oral systemic bioavailability of pergolide mesylate is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of ¹⁴C radio-labeled pergolide mesylate, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO₂, suggesting that a significant fraction is absorbed. Data on post absorption distribution of pergolide are unavailable.

[0008] Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide mesylate is co- administered with other drugs known to affect protein binding.

[0009] U.S. Pat. No. 4,797,405 which is incorporated herein by reference discloses that pergolide decomposes upon exposure to light to sulfoxide species. As a result, it is necessary to handle the compound and store the ultimate dosage form in a light-controlled environment so as to avoid a demonstrable drop in potency of the therapeutic agent. In order to retard this drop in potency, certain stabilizing agents have been incorporated into pharmaceutical compositions containing pergolide to reduce decomposition when exposed to light. Each of U.S. Pat. Nos. 4,797,405 and 5,114,948 disclose various stabilizing agents that purportedly retard decomposition to sulfoxide. However, beyond addition of stabilizing additives, the references fail to remedy the decomposition problem.

SUMMARY OF THE INVENTION

[0010] The present invention provides for stable pergolide mesylate in dry dosage form and in therapeutically effective amount without the addition of stabilizing compound. A process for manufacturing stable pergolide mesylate is also provided for both dry and wet granulates. The pergolide mesylate compound produced according to the invention is found to be substantially stable even without the presence of stabilizing compounds.

DETAILED DESCRIPTION

[0011] The embodiments of the present invention are described according to the following examples. The advantages of the invention are illustrated by way of comparative data in tables that follow.

EXAMPLE 1 Wet Granulation

[0012] A. 0.05 mg Tablets Pergolide Mesylate 0.065 mg* Lactose Monohydrate NF 157.565 mg Microcrystalline Cellulose NF 80.0 mg Pregelatinized Starch NF 30.0 mg Sodium Starch Glycolate NF 30.0 mg Magnesium Stearate NF 2.25 mg Color Ferric Oxide NF 0.12 mg Purified Water USP (processing solvent only) Alcohol USP 95% (processing solvent only) TOTAL 300.0 mg B. 0.25 mg Tablets Pergolide Mesylate 0.325 mg** Lactose Monohydrate NF 156.575 mg Microcrystalline Cellulose NF 80.0 mg Pregelatinized Starch NF 30.0 mg Sodium Starch glycolate NF 30.0 mg Magnesium stearate NF 2.25 mg Color ferric Oxide NF 0.65 mg Color FDC Blue No. 2 0.2 mg Purified Water USP (processing solvent only) Alcohol USP 95% USP (processing solvent only) TOTAL 300.0 mg C. 1.0 mg Tablets Pergolide Mesylate 1.3 mg*** Lactose Monohydrate NF 155.95 mg Microcrystalline Cellulose NF 80.0 mg Pregelatinized Starch NF 30.0 mg Sodium Starch Glycolate NF 30.0 mg Magnesium Stearate NF 2.25 mg Color Ferric Oxide NF 0.5 mg Purified Water USP (processing solvent only) Alcohol USP 95% (processing solvent only) TOTAL 300 mg

[0013] Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and the colors were mixed in a high speed mixer. Pergolide mesylate was dissolved in a mixture of purified water and alcohol USP (1:3). The granulation was performed by adding pergolide mesylate solution to the powder mixture. The wet granulation was dried in a fluid bed drier at 50° C., using an air flow of 200-500 m³/h/kg for 30-60 minutes (LOD: 0.5-2.5%). Once dry, the granulates were milled. Thereafter, magnesium stearate was added to the milled granulate and mixed. The final blend was compressed into oval shaped tablets on a rotary tableting machine (batch size ca. 7 Kg tablets).

[0014] Stability studies were initiated at accelerated conditions (40° C. and 75% relative humidity) for three months and compared with Permax® (Atena) tablets. The following stability results were obtained: TABLE 1 Stability study of 0.05 mg pergolide tablets prepared according to the principles of the invention. Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 99.4 1.1 <0.05 3 Mo. 94.2 4.8 1.3

[0015] TABLE 2 Permax ® (0.05 mg) Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 100.0 1.7 0.3 3 Mo.  95.9 3.6 0.4

[0016] TABLE 3 Stability study of 0.25 mg pergolide tablets prepared according to the principles of the invention. Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 103.1 0.3 <0.5 3 Mo.  99.3 1.3  0.5

[0017] TABLE 4 Permax ® (0.25 mg) Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 104.6 2.0  0.1 3 Mo. 100.6 3.6 <0.1

[0018] TABLE 5 Stability study of 1.0 mg pergolide tablets manufactured according to the principles of the invention. Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 103.3 0.1  0.4 3 Mo. 99 <0.05 <0.1

[0019] TABLE 6 Permax ® (1.0 mg) Degradation Products (%) Total Degradation (excluding Products (%) pergolide Interval Assay (%) Pergolide Sulfoxide Sulfoxide) 0 Mo. 103.8 0.9 0.1 3 Mo.  98.1 1.9 0.1

EXAMPLE 2 Dry Granulation

[0020] Each 0.05 mg pergolide tablet contains: Pergolide Mesylate 0.065 mg* Lactose Monohydrate NF 117.835 mg Microcrystalline Cellulose NF 60.0 mg Pregelatinized Starch NF 30.0 mg Sodium Starch Glycolate NF 30.0 mg Magnesium Stearate NF 2.0 mg Color Ferric Oxide NF 0.1 mg TOTAL 240.0 mg

[0021] Pergolide mesylate was mixed in a suitable container with lactose monohydrate microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, color ferric oxide and ⅓ of the magnesium stearate quantity. The powder mixture was compressed in a slug tableting machine. The slug tablets were milled and mixed with the rest of the magnesium stearate. The powder mixture was compressed into oval shaped tablets on a rotary tableting machine (batch size 140,000 tabs.) Analytical results were as follows:

[0022] Uniformity of content: 97.6%; RSD 3.5%

[0023] Uniformity of blend: 97.5%; RSD 1.0%

[0024] Stability studies were initiated at accelerated conditions (40° C. at 75% relative humidity for three months). The results are tabulated in Table 7, 8 and 9. TABLE 7 Stability of 0.05 mg pergolide dry tablets. Degradation Degradation products (%) products (%), total (Pergolide (excluding Interval Assay (%) sulfoxide) pergolide sulfoxide) 0 Mo. 98.8 0.5 <0.1 3 Mo. 91.4 2.4 <0.1

[0025] TABLE 8 Stability of 0.25 mg Pergolide dry tablets. Degradation Degradation Products (%), total Products (%) excluding pergolide Interval Assay (%) (Pergolide Sulfide) sulfide. 0 Mo. 96.2 0.1 <0.1 3 Mo. 95.0 0.8 <0.1

[0026] TABLE 9 Stability of 1 mg pergolide dry tablets. Degradation Pergolide Products Products (%), total (% pergolide excluding pergolide Interval Assay (%) sulfoxide) sulfoxide 0 Mo. 97.0 <0.1 <0.1 3 Mo. 96.2 0.2 <0.1 

1. A method for manufacturing pergolide mesylate comprising: forming a powder mixture having lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch, glycolate; dissolving pergolide mesylate in water and alcohol to form a pergolide mesylate solution; forming a wet granulation by adding the pergolide mesylate solution to the powder mixture; drying the wet granulation to form dry granulate; milling the dry granulate to form milled granulate; mixing magnesium stearate with milled granulate to form a blend.
 2. The method of claim 1, wherein pergolide mesylate is dissolved in water and alcohol having a ration of 1 to
 3. 3. The method of claim 2, wherein said drying step is carried out in a fluid bed drier.
 4. The method of claim 3, wherein the fluid bed dryer uses an airflow of 200 to 500 m³/h/kg.
 5. The method of claim 1, further comprising the step of compressing said blend into tablets.
 6. A pergolide mesylate in therapeutically effective amount and in unit dry dosage form which degrades to pergolide sulfoxide less than 4.8% after three month of storage at 40° C. and 75% relative humidity.
 7. The pergolide mesylate of claim 6, wherein the amount of total degradation to pergolide sulfoxide does not exceed 1.3%.
 8. The pergolide mesylate of claim 6, wherein said pergolide mesylate does not contain stabilizers.
 9. A pergolide mesylate composition initially containing 0.3% pergolide sulfoxide and containing 1.3% pergolide sulfoxide after 3 months storage at 40° C. and 75% relative humidity.
 10. The pergolide mesylate composition of claim 8, wherein said composition does not contain stabilizer.
 11. A pergolide mesylate composition as produced according to claim
 1. 12. A method for manufacturing stable pergolide mesylate comprising: forming a powder mixture having lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, color ferric oxide and magnesium stearate; compressing the powder mixture into at least one slug tablet; milling the rotary tablets; and mixing the milled rotary tablets with magnesium stearate to produce stable pergolide mesylate.
 13. The method of claim 12, wherein the step of compressing the powder mixture is accomplished by a rotary tableting machine.
 14. The method of step 12, further comprising compressing the stable pergolide mesylate into tablets.
 15. The method of claim 12, wherein the stable pergolide mesylate initially contains less than 0.5% pergolide sulfoxide. 